SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells
- The Institute of Cancer Research, London, United Kingdom
- CIC bioGUNE, Spain
Abstract
SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.
Data availability
Sequencing data have been deposited in ArrayExpress as accession E-MTAB-9108. All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Breast Cancer Now (Programme Funding to the Breast Cancer Now Toby Robins Research Centre)
- Erik Oliemuller
- Richard Newman
- Siu Man Tsang
- Gareth Muirhead
- Farzana Noor
- Syed Haider
- Beatrice A Howard
Cancer Research UK (CRUK: A21855)
- Shane Foo
Spanish Ministry of Education and Science (SAF2017-84934-R)
- Maria dM Vivanco
Government of the Autonomous Community of the Basque Country, the Department of Industry, Tourism and Trade
- Iskander Aurrekoetxea-Rodríguez
- Maria dM Vivanco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was carried out under UK Home Office PPL number: PB0FA698C (BAH Project licence holder) and personal licenses following local ethical approval of all protocols from The Institute of Cancer Research Ethics Committee and in accordance with local and national guidelines. All surgery was performed under isoflurane anesthesia with appropriate analgesia, and every effort was made to minimise suffering.
Copyright
© 2020, Oliemuller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells
eLife 9:e58374.
https://doi.org/10.7554/eLife.58374
Further reading
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Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.
